Is BAP1 p.Glu125Asp (c.375G>C) pathogenic?

BAP1 p.Glu125Asp (c.375G>C) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-25). AlphaMissense: likely pathogenic (0.7248); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.Glu125Asp (c.375G>C)?

BAP1 p.Glu125Asp (c.375G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Glu125Asp (c.375G>C) in the general population?

BAP1 p.Glu125Asp (c.375G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BAP1 p.Glu125Asp (c.375G>C)?

AlphaMissense predicts likely pathogenic (score 0.7248) — an in-silico prediction, not a clinical call.

BAP1 p.Glu125Asp

c.375G>C · VCV3477532

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7248 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7248	likely pathogenic
REVEL	0.247	benign-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.90	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.88	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BAP1
Protein: p.Glu125Asp
Coding: c.375G>C
MANE Select: NM_007212 · reported on NM_004656
Type: single nucleotide variant
Location: chr3:52407958 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB
Residue 125: the 'interaction with hip2' region

Full BAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BAP1 p.Glu125= Pathogenic ★ same residue
BAP1 p.Glu125Lys Uncertain significance ★ ⚠ same residue
BAP1 c.1117-1G>A Likely pathogenic ★★ same condition
BAP1 c.122+1G>A Pathogenic ★★ same condition
BAP1 c.122+1G>T Pathogenic/Likely pathogenic ★★ same condition
BAP1 c.1251-1G>A Likely pathogenic ★★ same condition
BAP1 c.1251-2A>G Likely pathogenic ★★ same condition
BAP1 c.1729+1G>A Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/bap1-p-glu125asp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown